Perspectives of the Friedreich ataxia community on gene therapy clinical trials

Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.


INTRODUCTION
2][3] Although FA is a rare disease, it is the most common hereditary ataxia, affecting an estimated 1 in 20,000 individuals of Western European ancestry. 4The typical onset of disease is before age 15 years, and patients exhibit some combination of gait and limb ataxia, loss of coordination, fatigue, scoliosis, dysphagia, hearing loss, vision loss, saccadic eye movements, and cardiac involvement. 5,6Patients typically require the use of a wheelchair within 5-10 years of diagnosis and eventually require assistance with all activities of daily living in later stages of the disease. 5,6The cardiac disease associated with FA, cardiomyopathy, affects approximately 60% of patients and is typically fatal, putting the median age of death at 35 years. 7,8Patients with an onset of disease after age 25 (late-onset FA) generally have a less severe course of progression, with an absence of scoliosis and cardiac involvement. 1 As of now, there is one recently US Food and Drug Administration (FDA)-approved treatment for FA, omaveloxolone (Skyclarys). 9owever, there are no FDA-approved treatments that target the root etiology: low levels of frataxin. 10The lack of treatments targeting the root etiology presents a substantial unmet medical need.
There is interest in the development of a gene replacement therapy (referred as gene therapy hereafter) to provide a healthy copy of the FXN gene and in theory, restore frataxin protein to a nonpathogenic level.Several investigational gene therapies are currently in preclinical and clinical development for FA that differ in their desired treatment target, the area that a therapeutic is designed to reach.Different vectors and routes of administration can be used to target different areas of the body. 11Since FA is a multisystem disease, the choice of treatment target presents a challenge for gene therapy.Different routes of administration may be required to treat cardiac and nervous system involvement.The main sites of neurodegeneration in FA are the dentate nucleus of the cerebellum and the dorsal root ganglia of the spinal cord. 12There is debate on the timing of damage to these structures relative to disease course, creating difficulty in determining the disease stage at which treatment of these structures would no longer rescue function. 13,14 addition to the challenges presented by treatment target, there are many other factors that may need consideration in gene therapy trial design for FA; particular factors include inclusion/exclusion criteria; length of trial; burden on patient/caregiver related to location of the trial and procedures; risks associated with dose, immunomodulation, and administration method; patient acceptance/aversion to these risks; patient perspective of disease burden; and availability of other trials.As a consequence, it is vital to consider the patient perspective in gene therapy clinical trial design.
Fortunately, other disease communities undergoing gene therapy clinical trials, notably the Duchenne muscular dystrophy (DMD) community, have previously published research on understanding the patient perspective of gene therapy that provides an important foundation for our work.The first DMD study consisted of qualitative interviews that revealed how patients and caregivers felt about gene therapy, including risk acceptance and therapeutic expectations/priorities.The authors found through thematic analysis that these answers were influenced by the state of disease progression, with different therapeutic priorities and a higher level of risk acceptance associated with more severe disease. 15The next DMD study was designed as a best-worst scaling questionnaire, asking participants to rank what they cared about most to least when choosing to participate in an early-phase gene therapy trial.The results indicated that participants prioritized potential benefits over potential harm and painful procedures. 16Finally, Peay et al. designed a study in which gene therapy was described in a scenario as noncurative, with the effect of slowing progression for 10 years.Patients' and caregivers' maximum acceptable risk of mortality was then assessed for the initiation of gene therapy at different stages of disease progression.The authors discovered a relatively high tolerance for mortality risk overall that paralleled disease progression. 17nce FA has both shared and unique gene therapy trial design challenges, it is important to define the preferences specific to the FA community.This was designed as a descriptive pilot study to acquire results that could guide the design and development of future studies; however, we were also interested in testing the hypothesis that responses will differ between patients and parents/caregivers.This research is also crucial for the ongoing development of FA gene therapies.In a recent FDA Patient-Focused Drug Development listening meeting, the FDA expressed their desire for more formal research into patient perspectives on gene therapy and the incorporation of these data into trial design. 18

Demographics
The summary statistics for the survey participants and the FA patients captured in the survey are outlined in Tables 1 and 2. For parent/caregiver responses, demographic information such as age and gender refers to the FA patient for whom the parent/caregiver is caring.Notably, the mean ages of onset and diagnosis do not accurately describe the sample due to a few higher-age outliers that create a skew in the distribution (Figure 1).The median ages of diagnosis (15 years) and onset (11 years) better describe our sample as representative of early-onset, or classical, FA.

Symptoms
Participants were asked what their/the patient's first symptom was, which symptom most interferes with quality of life, and which symptom they would prefer to treat if only one could be treated.Patients with FA reported that their first symptom was balance/inability to walk (48.9%), impaired coordination (26.1%), or scoliosis (18.2%).Parents/caregivers of a patient with FA reported that their patient's first symptom was cardiomyopathy/heart problems (38.8%),balance/inability to walk (32.7%), or impaired coordination (28.6%).The distribution of responses for first symptom was significantly different between patients and parent/caregivers responding about their patient, c 2 (7) = 19.28,p < 0.01.Quality of the patient's life was reported to be most affected by balance/inability to walk in 77.3% of self-reporting patients and 75.5% of parents/caregivers.Likewise, if only one symptom could be treated, then balance/inability to walk was chosen by 76.1% of patients and 71.4% of parents/caregivers.Although not statistically significant, it is notable that cardiomyopathy was chosen to be the treated symptom by 1.1% of patients and 10.2% of parents/caregivers (Figure 2).

Participant education
Before beginning the survey, participants were provided with a brief educational document that gave an overview of gene therapy and FA.A total of 71.6% of patients and 85.7% of caregivers agreed or strongly agreed that their knowledge of gene therapy improved after reviewing this educational introduction (Figure 3).The other participant education questions revealed that individuals with FA and caregivers feel knowledgeable about scientific advances in FA, different types of clinical trials, and gene therapy.Notably, there were significant differences in the level of agreement in responses from patients and parents/caregivers to the items "prior to the survey, I was knowledgeable about different types of clinical trials," z = 2.35, p = 0.02, and "I am aware of scientific advances in FA," z = 3.17, p < 0.01 (Figure 3).
The majority of participants reported that they learn about advances in FA research and upcoming clinical trials through patient advocacy organizations and the Internet.Less than half report learning this information from their healthcare providers (Figure 3).

Clinical trial perceptions
There were significant differences in the level of agreement in responses from patients and parents/caregivers to the items "I believe clinical trials are important for scientific research," z = 2.86, p < 0.01, and "I believe clinical trials are necessary to study the treatment effects for FA," z = 2.91, p < 0.01 (Figure 4).There was also a significant difference in the level of agreement in responses from patients and parents/caregivers to the item "I believe that clinical trials for FA are focused on patient medical needs," z = 2.27, p = 0.02 (Figure 4).
A total of 49.4% of patients and 50.0% of parents/caregivers agree or strongly agree that patient preferences are incorporated in clinical trials for FA, whereas 76.7% of patients and 87.8% of parents/caregivers agree or strongly agree that they would be comfortable sharing these preferences about clinical trial study design (Figure 4).Lastly, 44.8% of patients and 52.1% of caregivers agree or strongly agree that they would be more likely to join a trial if researchers considered their preferences about the study design (Figure 4).

FA gene therapy perceptions
Respondents were first asked about their expectations of gene therapy for FA.For patients, 60.0% believe that gene therapy will reduce their symptoms, 59.5% anticipate that gene therapy will prevent their symptoms from worsening, and 25.0% believe that gene therapy is curative (Figure 5).For parents/caregivers, 63.3% believe that gene therapy will reduce symptoms, 67.4% anticipate that gene therapy will prevent symptoms from worsening, and 20.4% believe that gene therapy is curative (Figure 5).
There was a significant difference in the level of agreement in responses from patients and parents/caregivers to the item "I understand that gene therapy has risks," z = 2.73, p % 0.01 (Figure 5).Respondents were also asked whether they believe the most severe FA patients, mildly affected FA patients, or children should be treated first.There was a significant difference in the level of agreement in responses from patients and parents/caregivers to the item "I believe mildly affected patients with FA should be treated first," z = 2.29, p = 0.02, and no significant differences between respondents to the items "I believe the most severe patients with FA should be treated first" and "children with FA should be treated with gene therapy before adult patients" (Figure 5).

Factors influencing participation in gene therapy
Participants were asked a variety of questions about factors that may influence their participation in a gene therapy clinical trial.There were no significant differences in the level of agreement in responses from patients and parents/caregivers to these items.A total of 64.0% of patients and 59.0% of parents/caregivers neither agree nor disagree that they would prefer not to be treated with immunomodulation medicines in a gene therapy study (Figure 6).A total of 36.8% of patients and 40.8% of parents/caregivers agree or strongly agree that they would join a gene therapy study regardless of whether they were treated with immunomodulation medicines, and 49.4% of patients and 44.9% of parents/caregivers are ambivalent about this question (Figure 6).A total of 43.2% of patients and 49.0% of parents/caregivers neither agree nor disagree that the vector dose would not matter to them, whereas 35.2% of patients and 34.7% of parents/caregivers agree or strongly agree that the vector dose would not matter to them (Figure 6).
We then asked whether people would prefer to be treated immediately even if they would receive a lower dose, or if they preferred to be treated later if it meant they could receive a higher dose.A total of 46.6% of patients and 36.7% of parents/caregivers would prefer to be treated immediately even if it meant they would receive a lower dose, and 34.1% of patients and 51.0% of parents/caregivers were ambivalent (Figure 6).A total of 39.1% of patients and 30.6% of parents/caregivers would prefer to be treated later if they could receive a higher dose, and 43.7% of patients and 61.2% of parents/caregivers were ambivalent (Figure 6).
A total of 26.1% of patients and 12.2% of parents/caregivers would not join a gene therapy study if it meant they/their child could not receive gene therapy again in the future, whereas 44.3% of patients and 44.9% of parents/caregivers indicated that they would (Figure 6).Meanwhile, 45.5% of participants with FA and 39.6% of caregivers agreed or strongly agreed that they would join a gene therapy study regardless of the consequences and possible side effects (Figure 6).
Finally, we inquired about external factors that may influence the decision to participate; 37.5% of patients and 53.1% of parents/caregivers responded that the time commitment would not influence their decision to participate, whereas 36.8% of patients and 22.5% of parents/caregivers indicated that time commitment would be a factor.The availability of upcoming trials would be more influential as 60.2% of patients and 63.7% of parents/caregivers agreed or strongly agreed that would influence their decision to participate (Figure 6).

DISCUSSION
A strong majority of our sample reported feeling knowledgeable about gene therapy before the survey and having an increase in knowledge about gene therapy following reading the provided educational material in the survey introduction.Despite this perceived knowledge, the ambivalence about immunomodulation and the vector dose appears to indicate a lack of understanding about these topics.As we anticipated for this progressive disease with unmet medical need, there is a clear sense of urgency in obtaining gene therapy regardless of the consequences and possible side effects.We expected the proportion of respondents who would disregard risk to be higher among individuals with FA than caregivers of children with FA; however, there was no significant difference.Instead, we found a significant difference between patients and parents/caregivers in their understanding that gene therapy has risks.This raises the question of what risks patients and caregivers attribute to gene therapy.
The perceptions about FA gene therapy captured in our survey revealed high expectations for efficacy.Currently, there are no data in existence on the effect of gene therapy, for any tissue target, on human FA patients.Therefore, the spectrum of outcomes of gene therapy in this patient population are unknown.Our data suggest that people in the FA community are anticipating that gene therapy will have a substantial disease-modifying effect.This is an important finding for stakeholders who are creating patient education materials.It is also worth inquiring whether the high therapeutic expectations have contributed to the large proportion of respondents who would join a gene therapy study regardless of the consequences and possible side effects.
Furthermore, there is a considerable amount of ambivalence regarding whether the most severe FA patients, mildly affected FA patients, or children should be treated first.Respondents were generally in agreement that severe patients should be treated first.There was substantial uncertainty about whether children should be treated before adults.There was a significant difference in patient and parent/caregiver responses regarding whether mildly affected FA patients should be treated first.These responses may be due to the differences in the perceived risk of gene therapy and the high therapeutic expectations.The availability of the "neither agree nor disagree" option made it difficult to ascertain how participants really felt about who should be dosed first.
The patients' perceived symptom burden revealed another interesting finding.Cardiac complications present the most common cause of mortality in FA and are prevalent in childhood-onset classical FA, a population that is predominantly represented in this study.Despite this, respondents reported that their neurological symptoms most interfere with their quality of life and, overwhelmingly, that they would choose to treat these neurological symptoms over cardiac symptoms, if they could choose only one target symptom to treat.This is suggestive that individuals with FA prioritize an improved quality of life over an increased life expectancy.Although not significant, a higher proportion of caregivers than participants with FA would choose to treat cardiomyopathy, supporting the idea that patients may place higher value on quality of life over being alive.This conclusion is important for the prioritization of patient perspectives in research and drug development, especially because several FA gene therapies are in development with different treatment targets. 9However, it is limited in that the survey did not include a question inquiring whether the patient has cardiac complications of FA.Although we can assume from the ages of onset and diagnosis that cardiac complications are present in the patients captured in the dataset, it could be possible that these patients do not experience cardiac complications.This could explain the decision not to treat it if they could only choose one symptom.Further research will be needed to explore this concept.
Participants reported that their decision to participate in a gene therapy clinical trial would be more strongly influenced by the options of other available and upcoming trials than by the time commitment required to participate in the trial.Many gene therapies or other treatments for FA are currently in development, which could increase the options of available and upcoming trials.Consequently, patients who meet the eligibility criteria for multiple trials will inevitably need to choose between participation in each of these trials.It is important to note that the time commitment will not be as heavy of an influence on the decision to participate since gene therapy trials will be longer than traditional clinical trials.This presents encouraging data that the increased length of gene therapy trials will not discourage participation.
It is interesting that although both patients and parents/caregivers strongly feel that "clinical trials are important and necessary" and "clinical trials for FA are focused on patient medical needs," parents/caregivers feel significantly more strongly about these statements than patients.Further investigation is required to explore these differences.The FA community is more ambivalent regarding whether patient preferences are incorporated into trials or whether this would affect decision to join a trial; however, most participants would feel comfortable sharing their preferences, if asked.
Finally, our sample felt strongly that they are educated about scientific advances and upcoming clinical trials for FA.The Internet and patient advocacy organizations are more influential in providing this information to respondents than healthcare providers.This finding, however, is limited by the nature of recruitment (e-mail distribution via a patient organization's patient registry may bias the responses in favor of patient advocacy organizations).The nature of recruitment may also represent an overall limitation since it is unclear how representative the sample is of the overall population of the FA community in the United States.The mix of agreement and disagreement within both groups that healthcare providers provide information about upcoming clinical trials is interesting and may point to the fact that FA is a rare disease and, subsequently, there are a limited number of providers with clinical expertise in FA.These are relevant data for clinical trial recruitment.
In summary, the findings from this preliminary study of the FA community's perception of gene therapy trials offer insight into the education level of the community on gene therapy, their therapeutic expectations, and their perception of the disease burden.These data also highlight how the FA community obtains information about scientific advances in FA and upcoming clinical trials.Our study also indicates that the FA community would be comfortable sharing their preferences for clinical trial design.Lastly, this study identifies some differences in thought between patients and parents/caregivers.A potential limitation of our study is the inclusion of the educational document.It is unclear how any of the information in this document may have influenced survey responses, if at all.Our findings represent important information for stakeholders regarding clinical trial design and community education, which is crucial for patient-focused drug development.Individuals interested in voluntary participation were directed to the IRB-approved informed consent.Participants were instructed to read the consent in its entirety.At the bottom of the page, the participants were instructed to electronically consent to participate via "Yes" or "No" selections.Due to the required anonymity of the study, participants did not indicate their name nor their location on the consent, meaning there were no screening mechanisms.Following agreement, the participant was instructed to move to the next page to begin the questionnaire.Only once consent/assent was obtained could the participant continue to the questionnaire.Participants were electronically provided with a copy of the consent document for their personal records.The survey was conducted through the Internet using the browserbased, electronic data collection service REDcap between March 8, 2022 and April 18, 2022.The survey included a few questions about age, diagnosis, onset, and symptoms.Participants then answered Likert-style questions ranging from "strongly agree" to "strongly disagree" regarding a variety of topics related to gene therapy and clinical trials.A full copy of the survey is available in the supplemental information.

MATERIALS AND METHODS
The directions stated that the following individuals could participate in the survey: parents/caregivers of children with FA younger than 14 years, patients 14 years and older, and parents/caregivers of children with FA aged 14-17 years collaboratively with their children.A total of 156 records were saved; however, 15 of these were incomplete.Thus, 141 complete records were included for preprocessing.This is a response rate of 30.0%.All of the patient records came from pa-tients with a current age of 14 years or older, as intended by the directions.A total of 35% (18/52) of the parent/caregiver records came from parents/caregivers of a patient currently 18 years or older, which was not indicated by the directions.Rather than excluding this large proportion of data, the category for analysis was adjusted to include parent/caregivers of patients who were diagnosed with FA as a child (regardless of their current age).Thus, we only excluded 4 complete records, which were from parent/caregivers of patients who were diagnosed with FA as adults.The final number of records for analysis was 137.Data quality was reviewed for validity by 3 authors and an external contributor.

Data analysis
Summary statistics were generated using Microsoft Excel, and figures were generated using Microsoft Excel and GraphPad Prism.For statistical analysis, participants were divided into two comparison groups in terms of the question "who is completing this survey?":patients with FA and parents/caregivers of an individual with FA who was diagnosed as a child.For the questions with nominal categorical responses, c 2 exact tests were performed to detect the differences between the two groups.For the questions with Likert scale responses, items were first converted into an ordinal scale and Mann-Whitney tests were then performed.Items with a p < 0.05 were considered significant.Statistical analysis was implemented with SAS (version 9.4, SAS Institute, Cary, NC).

Figure 1 .
Figure 1.Ages of diagnosis and onset This violin plot displays the age distribution of FA patients captured in the survey at disease onset and diagnosis.

Figure 2 .
Figure 2. Perception of symptom burden This 100% stacked bar chart represents participants' answers to 3 survey questions regarding symptom burden.The total number of respondents (n) is indicated next to each survey item.Items with a significantly different proportion of responses are indicated by an asterisk (*).

Figure 3 .
Figure 3. Participant education This bidirectional 100% stacked bar chart represents patients' and caregivers' responses to survey questions regarding their education level on FA clinical trials.The proportions of patient responses are represented by the negative x axis and the proportions of caregiver responses are represented by the positive x axis.The total number of respondents (n) is indicated next to each survey item.Items with a significantly different proportion of responses are indicated by an asterisk (*).

Figure 4 .
Figure 4. Clinical trial perceptions This bidirectional 100% stacked bar chart represents patients' and caregivers' responses to survey questions regarding their clinical trial perceptions.The proportions of patient responses are represented by the negative x axis and the proportions of caregiver responses are represented by the positive x axis.The total number of respondents (n) is indicated next to each survey item.Items with a significantly different proportion of responses are indicated by an asterisk (*).

Figure 5 .
Figure 5. Gene therapy perceptions This bidirectional 100% stacked bar chart represents patients' and caregivers' responses to survey questions regarding their FA gene therapy perceptions.The proportions of patient responses are represented by the negative x axis and the proportions of caregiver responses are represented by the positive x axis.The total number of respondents (n) is indicated next to each survey item.Items with a significantly different proportion of responses are indicated by an asterisk (*).

Figure 6 .
Figure 6.Factors influencing participation in gene therapy This bidirectional 100% stacked bar chart represents patients' and caregivers' responses to survey questions regarding the factors that would influence their participation in a gene therapy clinical trial.The proportions of patient responses are represented by the negative x axis and the proportions of caregiver responses are represented by the positive x axis.The total number of respondents (n) is indicated next to each survey item.There are no items with significantly different proportions of responses.

Table 1 .
Demographics of the survey participants

Table 2 .
Demographics of the FA patients captured in the survey